Findings Published in Nature Could Lead to Drugs that Thwart
Outbreaks

BRONX, N.Y., Aug. 24, 2011 /PRNewswire-USNewswire/ --
Researchers at Albert Einstein College of
Medicine of Yeshiva University have helped identify a cellular
protein that is critical for infection by the deadly Ebola virus.
The findings, published in today's online edition of Nature,
suggest a possible strategy for blocking infection due to Ebola
virus, one of the world's most lethal viruses and a potential
bioterrorism agent.

The study was a collaborative effort involving scientists from
Einstein, the Whitehead Institute for Biomedical Research, Harvard
Medical School, and the U.S. Army Medical Research Institute of
Infectious Diseases.

Ebola virus is notorious for killing up to 90 percent of the
people it infects. Ebola hemorrhagic fever â€“ the
severe, usually fatal disease that Ebola virus causes in humans and
in nonhuman primates â€“ first emerged in 1976 in
villages along the Ebola River in the Sudan and the Democratic
Republic of the Congo, Africa. Since then, about two dozen
outbreaks have occurred.

Though Ebola and Marburg hemorrhagic fevers are fortunately rare
diseases, "even small outbreaks of Ebola or Marburg virus can cause
fear and panic," said co-senior author Kartik Chandran, Ph.D., assistant
professor of microbiology &
immunology at Einstein "And then there's the worry that these
viruses could be used for bioterrorism."

Ebola virus's ability to enter cells is reminiscent of the
Trojan Horse used by the ancient Greeks to defeat their
archenemies. Ebola virus binds to the host cell's outer membrane,
and a portion of host cell membrane then surrounds the virus and
pinches off, creating an endosome â€“ a
membrane-bound bubble inside the cell (see image). Endosomes carry
their viral stowaways deep within the cell and eventually mature
into lysosomes â€“ tiny enzyme-filled structures
that digest and recycle cellular debris.

The viruses captive in the lysosome manage to escape destruction
by exploiting components of the cell to gain entry to the
cytoplasm, the substance between the cell membrane and the nucleus
where the virus can replicate. But the identities of many of these
components have remained unknown.

In seeking the answer, Einstein researchers and colleagues
searched for proteins that Ebola virus might exploit to enter the
cell's cytoplasm. One such cellular protein, known as Niemann-Pick
C1 (NPC1), stood out.

"We found that if your cells don't make this protein, they
cannot be infected by Ebola virus," said Dr. Chandran. "Obviously
it's very early days, but we think our discovery has created a real
therapeutic opportunity." At present, there are no drugs available
to treat people who have been infected with Ebola virus or approved
vaccines to prevent illness."

The NPC1 protein is embedded within cell membranes, where it
helps transport cholesterol within the cell. However, the absence
of NPC1 due to gene mutations causes a rare degenerative disorder
called Niemann-Pick disease, in which cells become clogged up with
cholesterol and eventually die.

To confirm their finding that NPC1 is crucial for Ebola virus
infection, the researchers challenged mice carrying a mutation in
NPC1 with Ebola virus. Remarkably, most of these mutant mice
survived the challenge with this normally deadly virus. Similarly,
fibroblast cells (found in connective tissue) from people with
Niemann-Pick disease were resistant to Ebola virus infection, as
were human cells from other organs that were manipulated to reduce
the amount of NPC1 they contained.

The researchers also tested whether other major viruses need
NPC1 to infect human cells. Only Ebola virus and its close
relative, Marburg virus, were found to require the presence of NPC1
protein for infection. Like Ebola virus, Marburg virus also needs
NPC1 to kill mice.

"Our work suggests that these viruses need NPC1, which is
embedded in the lysosomal membrane, to escape from the lysosome
into the cytoplasm," said Dr. Chandran. "We are now testing that
hypothesis in the laboratory."

The discovery of NPC1's crucial role in Ebola infection raises
the possibility that Ebola and Marburg virus outbreaks could be
thwarted by a drug that blocks the action of NPC1. "Even though
such a treatment would also block the cholesterol transport
pathway, we think it would be tolerable," said Dr. Chandran. "Most
outbreaks are short-lived, so treatment would be needed for only a
short time." Einstein, in conjunction with the Whitehead Institute
of Biomedical Research and Harvard Medical School, has filed a
patent application related to this research that is available for
licensing to partners interested in further developing and
commercializing this technology.

Remarkably, an anti-Ebola virus inhibitor Dr. Chandran found as
a postdoctoral fellow at the Brigham and Women's Hospital in
Boston, MA, turns out to be just such an NPC1 blocker, as described
in a separate manuscript by Marceline Cote and co-workers to be
published in the same issue of Nature.

This research was supported by grants from the National
Institute of Allergy and Infectious Diseases and the National Human
Genome Research Institute, both part of the National Institutes of
Health; the U.S. Army; and the Burroughs Wellcome Fund.

Albert Einstein College of Medicine of Yeshiva University is one
of the nation's premier centers for research, medical education and
clinical investigation. In 2010, Einstein received nearly $200
million in support from the NIH for major research centers at
Einstein in diabetes, cancer, liver disease, and AIDS, as well
as other areas. Through its extensive affiliation network with five
medical centers, Einstein runs one of the largest post-graduate
medical training programs in the United States, offering
approximately 150 residency programs to more than 2,500 physicians
in training. For more information, please visit www.einstein.yu.edu

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